Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells are key immune effectors that eradicate infected cells and tumors. To destroy these targets, CTL and NK cells mostly use the granule exocytosis pathway which releases perforin and granzymes from cytolytic granules into the immunological synapse formed with the target. Granzyme B induces apoptosis through caspase-dependent and caspase-independent mechanisms. Granzyme is a serine protease that cleaves after aspartic acid residues and activates caspase-mediated apoptosis.
Granzyme B cleaves and activates the apical caspase, caspase 8, as well as caspases 3, 6, and 7. Granzyme B can directly activate caspase 3 and is capable of triggering apoptosis at multiple points of the caspase-dependent pathway and therefore is not absolutely dependent on caspase 8 cleavage. Granzyme B can also directly cleave BID. Truncated BID (tBID) then disrupts the outer mitochondrial membrane to cause release of the pro-apoptotic factors such as cytochrome C, which ultimately results in the proteolytic activation of caspase 3. Cells overexpressing natural inhibitors of caspases such as BCL2, CRMA and SPI2 are sensitive to granzyme B mediated apoptosis. Granzyme B also disrupts the mitochondrial transmembrane potential through an unknown mechanism and directly cleaves ICAD/DFF45 to cause DNA fragmentation. Also, the mitochondrial protein endo G, released by the action of granzyme B cleaved BID, can induce oligonucleosomal DNA damage. Therefore, granzyme B activates two routes to DNA damage, even when caspase activation is blocked.
In addition to targeting mitochondria and DNA degradation directly, granzyme B also directly cleaves several downstream caspase substrates. These include the DNA damage sensor PARP, double-strand DNA break repair protein DNA-PK, NUMA and the nuclear-envelope intermediate-filament protein lamin-B. Increased granzyme secretion has been implicated in the pathogenesis of rheumatoid arthritis, transplant rejection, asthma, atopic dermatitis, psoriasis and autoimmune disorders such as Sjogren's syndrome.